The ORL-1 (orphan opioid receptor) G-protein coupled receptor, also known as the nociceptin receptor, was first reported in 1994, and was discovered based on its homology with the classic delta-, mu-, and kappa-opioid receptors. The ORL-1 G-protein coupled receptor does not bind opioid ligands with high affinity. The amino acid sequence of ORL-1 is 47% identical to the opioid receptors overall, and 64% identical in the transmembrane domains. (Nature, 1995, 377, 532.)
The endogenous ligand of ORL-1, known as nociceptin, a highly basic 17 amino acid peptide, was isolated from tissue extracts in 1995. It was named both nociceptin, because it increased sensitivity to pain when injected into mouse brain, and orphanin FQ (OFQ) because of the terminal phenylalanine (F) and glutamine (Q) residues that flank the peptide on either side. (WO97/07212)
Nociceptin binding to ORL-1 receptors causes inhibition of cAMP synthesis, inhibition of voltage-gated calcium channels, and activation of potassium conductance. In vivo, nociceptin produces a variety of pharmacological effects that at times oppose those of the opioids, including hyperalgesia and inhibition of morphine-induced analgesia. Mutant mice lacking nociceptin receptors show better performance in learning and memory tasks. These mutant mice also have normal responses to painful stimuli.
The ORL-1 receptor is widely distributed/expressed throughout the human body, including in the brain and spinal cord. In the spinal cord, the ORL-1 receptor exists in both the dorsal and ventral horns, and precursor mRNA has been found in the superficial lamina of the dorsal horn, where primary afferent fibers of nociceptors terminate. Therefore, the ORL-1 has an important role in nociception transmission in the spinal cord. This was confirmed in recent studies wherein nociceptin, when given to mice by i.c.v. injection, induced hyperalgesia and decreased locomotor activity. (Brit. J. Pharmacol. 2000, 129, 1261.)
Adam, et al., in U.S. Pat. No. 6,071,925 (and in EP 0856514) disclose 1,3,8-triazaspiro[4,5]decan-4-one derivatives, agonists and/or antagonists of the OFQ receptor. More recently, Higgins, et.al., in European Forum of Neuroscience 2000, Brighton, U.K., Jun. 24–28, 2000, Poster 077.22 disclosed, 8-[(1R,3aS)-2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one useful as a cognition enhancers. Adam et al., in EP 921125-A1 disclose 1,3,8-triazaspiro[4.5]decan-4-one derivatives, agonists and/or antagonists of the OFQ receptor.
Ito, et al., in EP 0997464 disclose 1,3,8-triazaspiro[4.5]decan-4-one compounds as ORL-1 receptor agonists.
Watson, et al., in WO 99/59997 disclose 1,3,8-triazaspiro[4.5]decan-4-ones with high affinity for opioid receptor subtypes, useful for the treatment of migraine, type II diabetes, sepsis, inflammation, incontinence and/or vasomotor disturbance.
JP2000169476, assigned to Banyu Pharmaceutical Co., Ltd, disclose 4-oxoimidazolidine-5-spiro-nitrogen containing heterocyclic compounds which inhibit binding of nociceptin to the ORL1 receptor.
We now describe novel small molecule modulators of the ORL-1 receptor, useful for the treatment of disorders and conditions mediated by the ORL-1 receptor, such as anxiety, depression, substance abuse, neuropathic pain, acute pain, migraine, asthma, cough and for improved cognition.